Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is a genetic form of cardiomyopathy, which is typically characterized by right but also recently left ventricular dysfunction, fibrotic/fatty replacement of the ventricle and ventricular arrhythmias leading to sudden cardiac death. We have generated a mouse model of ARVD/C through conditional cardiac-specific ablation of the desmosomal component, desmoplakin, (desmo cKO) using the myosin-light chain-2v (MLC2v)-Cre mouse. Since MLC2v-Cre is expressed in a range of cardiomyocyte lineages, we propose to identify the subsets of myocyte populations contributing to the distinct phenotypic aspects observed in our model. Our model exhibits unique effects on connexin signaling, which are thought to play a key role in myocyte-myocyte and myocyte-fibroblast adhesion. Thus, we also propose to determine how defects in connexin signaling lead to changes in myocyte-myocyte and myocyte- fibroblast adhesion and contribute to phenotypic aspects of ARVD/C. Our model also exhibits cardiac cytosolic 2-catenin accumulation, which is an effect known to lead to aberrant 2-catenin nuclear translocation/ signaling. Thus, we propose to rescue our ARVD/C model by inhibiting 2-catenin's actions and signaling using a gene therapy approach. We also propose to assess the effects of inhibiting potassium ion channel and 2-adrenergic receptor actions in our ARVD/C model. The goal of this five-year proposal is to understand the cellular mechanisms underlying the various clinical features of ARVD/C as well as test the effects of current and new drug treatments as well as inhibiting 2-catenin's actions on the prognosis of our ARVD/C model. These results have led us to the hypotheses that desmoplakin plays an essential role in subsets of cardiomyocyte lineages and desmoplakin defects cause (i) connexin signaling defects which affect myocyte-myocyte and myocyte- fibroblast adhesion and mislocalization/loss of cell adhesion/junctional components, which affect myocyte cell fate and result in ARVD/C. Specific Aims include: (1) To determine the subset of cardiomyocytes responsible for ARVD/C, by ablating desmoplakin in distinct cardiomyocyte lineages. (2) To determine how connexin signaling affects myocyte-myocyte and myocyte-fibroblast adhesion in our model. (3) To rescue or alter the progression of ARVD/C in our model by inhibiting the actions of (a) 2-catenin's as well as the (b) K+ ion channel and 2-adrenergic receptor. PUBLIC HEALTH RELEVANCE: The goal of this five-year proposal is to (i) understand the cellular mechanisms underlying the various clinical features of the fatal human disease, arrhythmogenic right ventricular dysplasia/ cardiomyopathy (ARVD/C) and (ii) study the impact of manipulating molecular targets and administering current and new drug treatments for ARVD/C on the prognosis of a test mouse model, which we have generated to genetically carry the human disease ARVD/C. These studies will identify molecular pathways that are essential for the progression of ARVD/C and thereby improve our general understanding of this disease, as well as identify therapeutic targets for treating this fatal disease.